ES2548284T3 - Novel compounds as histamine H3 receptor ligands - Google Patents

Abstract

A compound of general formula (I): ** Formula ** in which at each occurrence, R 1 is independently selected from hydrogen, hydroxyl, hydroxyalkyl, halogen, alkyl, alkoxy, halogenoalkyl, halogenoalkoxy, cyano or -C (O) - NH2; ** Formula ** L is alkyl or; X is C, O or N-R2; Y is C or N; A is -C (O) - or -CH2; R2 is hydrogen, alkyl, -C (O) -alkyl or -S (O) 2-alkyl; "r" is an integer in the range of 0 to 1; "p" is an integer in the range of 0 to 3; or a pharmaceutically acceptable salt thereof.

Description

image 1

DESCRIPTION

Novel compounds as histamine H3 receptor ligands

Field of the Invention

The present invention relates to novel compounds of formula (I), their pharmaceutically acceptable salts and compositions containing them for the treatment of various disorders that are related to histamine H3 receptors.

image2

Background of the invention

The histamine H3 receptor is a G-protein coupled receptor (GPCR) and one of the four receptors of the

10 histamine family. The H3 histamine receptor is identified in 1983 and its cloning and characterization were performed in 1999. The H3 histamine receptor is expressed to a greater extent in the central nervous system and to a lesser extent in the peripheral nervous system.

Bibliographic evidence suggests that histamine H3 receptors can be used in the treatment of cognitive disorders (British Journal of Pharmacology, 2008, 154 (6), 1166-1181), dementia (Drug News

15 Perspective, 2010, 23 (2), 99-103), attention deficit hyperactivity disorder, epilepsy, sleep disorders, sleep apnea, obesity (Indian Journal of Pharmacology, 2001, 33, 17-28), schizophrenia (Biochemical Pharmacology, 2007, 73 (8), 1215-1224), eating disorders (Investigational drugs for eating disorders, 1997, 6 (4), 427-436) and pain (Pain, 2008, 138 (1), 61- 69).

Patent publications US 2009/0170869, US 2010/0029608, US 2010/0048580, WO 2009/100120, WO

20 2009/121812 and WO 2009/135842 have disclosed series of compounds as histamine H3 receptor ligands.

WO 2010/045306 discloses compounds for use in the treatment of diseases related to H3 histamine receptors. Although some histamine H3 receptor ligands have been released, to date no compound has been released in this research area, and there is still the

25 need and scope to discover new drugs with novel chemical structures for the treatment of disorders affected by histamine H3 receptors.

Summary of the invention

The present invention relates to novel histamine H3 receptor ligand compounds of formula (I)

image3

30 in which

at each occurrence, R1 is independently selected from hydrogen, hydroxyl, hydroxyalkyl, halogen, alkyl, alkoxy, halogenoalkyl, halogenoalkoxy, cyano or -C (O) -NH2

L is alkyl or X is C, O or N-R2;

image4

image5

Y is C oN; A is -C (O) -o -CH2; R2 is hydrogen, alkyl, -C (O) -alkyl or -S (O) 2-alkyl; "r" is an integer in the range of 0 to 1;

5 "p" is an integer in the range of 0 to 3; or a pharmaceutically acceptable salt thereof. The present invention relates to the use of a therapeutically effective amount of the compound of formula (I) for

manufacture a medication for the treatment of various disorders that are related to histamine H3 receptors. Specifically, the compounds of this invention are useful in the treatment of various disorders such as

10 cognitive disorders, dementia, attention deficit hyperactivity disorder, schizophrenia, epilepsy,

sleep disorders, sleep apnea, obesity, eating disorders and pain. In another aspect, the invention relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound of formula (I) and pharmaceutically acceptable salts thereof, in admixture with a pharmaceutically acceptable excipient.

The application includes procedures for using compounds of formula (I).

In yet another aspect, the invention further relates to the process for the preparation of compounds of formula (I) and their pharmaceutically acceptable salts. Representative compounds of the present invention include those specified below and their salts

pharmaceutically acceptable. The present invention should not be considered as limited to them.

N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (morpholin-4-yl) acetamide dihydrochloride; 2- [4- (1-Cyclobutylpiperidin-4-yloxy) phenylamino] -1- (morpholin-4-yl) ethanone hydrochloride; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-fluorophenyl] -2- (morpholin-4-yl) acetamide dihydrochloride; N- [4- (1-Cyclobutylpiperidin-4-yloxy) benzyl] morpholin-4-ylamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -3-fluorophenyl] -2- (morpholin-4-yl) acetamide;

N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-methylphenyl] -2- (3,3-difluoropyrrolidin-1-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-trifluoromethylphenyl] -2- (piperidin-1-yl) acetamide; N- [4- (1-Cyclopentylpiperidin-4-yloxy) phenyl] -2- (morpholin-4-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-trifluoromethylphenyl] -2- (morpholin-4-yl) acetamide; N- [4- (1-Isopropylpiperidin-4-yloxy) -2-methylphenyl] -2- (pyrrolidin-1-yl) acetamide;

N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-methylphenyl] -2- (pyrrolidin-1-yl) acetamide; N- [4- {1-Cyclopentylpiperidin-4-yloxy) -2-methylphenyl] -2- (piperidin-1-yl) acetamide; N- [4- {1-Cyclobutylpiperidin-4-yloxy) -2-methylphenyl] -2- (piperidin-1-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -N-methyl-2- (morpholin-4-yl) acetamide; N- [4- (1-Cyclopentylpiperidln-4-yloxy-2-methylphenyl] -2- (R-2-methylpyrrolidin-1-yl) acetamide;

N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-methylphenyl] -2- (R-2-methylpyrrolidin-1-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-methoxyphenyl] -2- (morpholin-4-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-trifluoromethylphenyl] -2- (4-hydroxypiperidin-1-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (4-hydroxypiperidin-1-yl) acetamide; N- [4- (1-Cyclopentylpiperidin-4-yloxy) -2-fluorophenyl] -2- (morphoIin-4-yl) acetamide dihydrochloride;

N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (pyrrolidin-1-yl) acetamide;

image6

N- [4- (1-Isopropylpiperidin-4-yloxy) phenyl] -2- (morpholin-4-yl) acetamide; N- [4- (1-Cyclopropylpiperidin-4-yloxy) phenyl] -2- (morpho-4-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- {4-isopropyl [1,4] diazepan-1-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (2-hydroxymethylmorpholin-4-yl) acetamide;

5 N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -3- (morpholin-4-yl) propionamide; N- [4- (1-Cyclopentylpiperidin-4-yloxy) phenyl] -2- (piperidin-1-yl) acetamide dihydrochloride; N- [4- (1-Cyclopentylpiperidin-4-yloxy) phenyl] -2- (pyrrolidin-1-yl) acetamide dihydrochloride; N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (piperidin-1-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-trifluoromethylphenyl] -2- (pyrrolidin-1-yl) acetamide dihydrochloride;

N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -N- {2-morpho-4-ylethyl) acetamide; [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] - (2-morpholin-4-ylethyl) amine; L (+) - N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (R-2-hydroxymethylpyrrolidin-1-yl) acetamide tartrate; N- [2- (1-Cyclobutylpiperidin-4-yloxy) pyridin-5-yl] -N- [2- (morpho-4-yl) ethyl] acetamide; N- [2- (1-Cyclobutylpiperidin-4-yloxy) pyridin-5-yl] -2- (piperidin-1-yl) acetamide;

N- [2- (1-Cyclobutylpiperidin-4-yloxy) pyridin-5-yl] -2- {morpho-4-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-fluorophenyl] -N- [2- (morpholin-4-yl) ethyl] acetamide; L (+) - N- [4- (1-cyclopropylpiperidin-4-yloxy) phenyl] -N- [2- (morpholin-4-yl) ethyl] acetamide N- [4- (1-cyclobutylpiperidine dihydrochloride) tartrate -4-yloxy) phenyl] -2- (1-acetylpiperazin-4-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-methylphenyl] -2- (4-hydroxypiperidin-1-yl) acetamide;

N- [4- (1-Cyclopropylpiperidin-4-yloxy) feniI] -2- (R-2-hydroxymethylpyrrolidin-1-iI) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) benzyl] -2- (morpholin-4-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-fluorobenzyl] -2- (morpholin-4-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (3-hydroxyazetidin-2-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy-2-fluorophenyl] -2- (3-methoxyazetidin-1-yl) acetamide;

N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-fluorophenyl] -2- (2-hydroxymethylpyrrolidin-1-yl) acetamide; N- [2-Chloro-4- (1-cyclobutylpiperidin-4-yloxy) phenyl] -2- (morpholin-4-yl) acetamide; N- [2-Chloro-4- (1-cic! Obutilpiperidin-4-yloxy) phenyl] -2- (piperidin-1-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (tetrahydropyran-4-yloxy) acetamide; 2- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-fluorophenylamino] -1- (morpholin-4-yl) ethanone and

N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-fluorophenyl] -N- (2-morpholin-4-ylethyl) acetamide.

Detailed description of the invention

Unless otherwise indicated, the following terms used in the specification and claims have the meanings given below:

The term "halogen" means fluorine, chlorine, bromine or iodine.

The term "alkyl" means straight or branched chain hydrocarbon radical consisting solely of carbon and hydrogen atoms, does not contain unsaturation, has 1 to 8 carbon atoms and is attached to the rest of the molecule by a single bond. Exemplary "alkyl" groups include methyl, ethyl, n-propyl, isopropyl and the like.

image7

The term "alkoxy" means an alkyl group attached through an oxygen bond to the rest of the molecule. Exemplary "alkoxy" groups include methoxy, ethoxy, propyloxy, isopropyloxy and the like.

The term "halogenoalkyl" means straight or branched chain alkyl radicals containing 1 to 3 carbon atoms. Exemplary "halogenoalkyl" groups include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, fluoroethyl, difluoroethyl and the like.

The term "halogenoalkoxy" means straight or branched chain alkoxy radicals containing 1 to 3 carbon atoms. Exemplary "halogenoalkoxy" groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, and the like.

The term "hydroxyalkyl" means that a hydroxyl group is attached directly to an alkyl chain. Exemplary "hydroxyalkyl" groups include hydroxymethyl, hydroxyethyl and the like.

The terms "treating", "treating" or "treatment" encompass all meanings such as preventive, prophylactic and palliative.

The phrase "pharmaceutically acceptable salts" indicates that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising a formulation with which it is being

15 treating the mammal.

The phrase "therapeutically effective amount" is defined as "an amount of compound of the present invention that (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, improves or eliminates one or more symptoms of the disease, particular condition or disorder or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein.

20 Commercial reagents were used without further purification. Ambient temperature refers to 25-40 ° C. Unless otherwise indicated, all mass spectra were carried out using ESI conditions. The 1 H-NMR spectra were recorded at 400 MHz in a Bruker instrument. Chloroform, methanol or deuterated dimethylsulfoxide was used as solvent. TMS was used as internal reference standard. The values of chemical displacement are expressed in values of parts per million (a). The following abbreviations are used for

25 multiplicity of NMR signals: s = singlet, sa = wide singlet, d = doublet, t = triplet, q = quartet, qui = quintet, h = heptete, dd = double doublet, dt = double triplet, tt = triple triplet, m = multiplet. Chromatography refers to column chromatography performed using 100-200 mesh silica gel and executed under nitrogen pressure conditions (flash chromatography).

Pharmaceutical compositions

To use the compounds of formula (I) in therapy, they will normally be formulated in a pharmaceutical composition according to standard pharmaceutical practice.

The pharmaceutical compositions of the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipient is a carrier or diluent. Thus, the active compounds of the invention can be formulated for oral, intranasal or

35 parenteral (eg, intravenous, intramuscular or subcutaneous). Such pharmaceutical compositions and the processes for preparing them are well known in the art ("The Science and Practice of Pharmacy", D.B. Troy, 21st edition, Williams & Wilkins, 2006).

The dose of the active compounds may vary depending on factors such as the route of administration, age and weight of the patient, nature and severity of the disease to be treated and similar factors. For the

Therefore, any reference herein to a pharmacologically effective amount of compounds of general formula (I) refers to the aforementioned factors. The proposed dose of the active compounds of this invention is for oral or parenteral administration to an average adult human being for the treatment of the conditions referred to above.

Preparation Procedures

The compounds of formula (I) can be prepared by Scheme I as shown below.

image8

Scheme I

In Scheme I above, B is OH, CI or Br and all other symbols are as defined above.

The compound of formula (1) is coupled with the compound of formula (2) forming the compound of formula (I). This

The reaction is preferably carried out in a solvent such as tetrahydrofuran, toluene, ethyl acetate, dichloromethane, dimethylformamide and the like or a mixture thereof, and preferably using dichloromethane and dimethylformamide. The reaction can be carried out in the presence of a base such as sodium hydride, sodium carbonate, potassium carbonate, diisopropylethylamine, sodium bicarbonate, sodium hydroxide or mixtures thereof, and preferably using potassium carbonate and diisopropylethylamine. The reaction can be carried out in

The presence of a coupling agent such as O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate. The reaction is carried out at a temperature of 25 to 85 ° C based on the choice of solvent and base. The duration of the reaction may range from 4 to 18 hours, preferably a period of 10 to 14 hours.

The compounds of formula (1) and formula (2) may be commercially available or may be prepared by conventional procedures or with modification, using known processes.

The compounds of formula (I) can also be prepared using Scheme II as shown below.

image9

Scheme II

In Scheme II above, all symbols are as defined above.

The compound of formula (1) is converted into the compound of formula (3). The compound of formula (3) 5 is coupled with the compound of formula (4), forming the compound of formula (I).

In the first stage of the previous preparation, the compound of formula (1) is converted into the compound of formula (3). This reaction is preferably carried out in a solvent such as tetrahydrofuran, toluene, ethyl acetate, dichloromethane, dimethylformamide and the like or a mixture thereof, and preferably using dichloromethane. The reaction can be carried out in the presence of a base such as triethylamine, potassium carbonate,

Diisopropylethylamine, pyridine and the like or a mixture thereof, and preferably using triethylamine. The reaction is carried out at a temperature of -10 to 10 ° C based on the choice of solvent and base. The duration of the reaction may range from 0.5 to 2 hours, preferably a period of 45 minutes to 1.5 hours.

In the second stage of the previous preparation, the compound of formula (3) is coupled with the compound of formula (4), forming the compound of formula (I). This reaction is preferably carried out in a solvent such as tetrahydrofuran, acetonitrile, toluene, ethyl acetate, dichloromethane, dimethylformamide and the like or a mixture thereof, and preferably using acetonitrile. The reaction can be carried out in the presence of a base such as triethylamine, potassium carbonate, diisopropylethylamine, pyridine and the like or a mixture thereof, and preferably using potassium carbonate. The reaction is carried out at a temperature of 25 to 85 ° C based on the choice of solvent and base. The duration of the reaction may range from 3 to 7 hours, preferably a

20 period from 4 to 6 hours.

The compounds of formula (1) and formula (4) may be commercially available or may be prepared by conventional procedures or with modification, using known processes.

The compounds of formula (I) can also be prepared using Scheme III as shown below.

image10

Scheme III

In Scheme III above, all symbols are as defined above.

The compound of formula (5) is coupled with the compound of formula (4), forming the compound of formula (6). The compound of formula (6) is converted into the compound of formula (I).

In the first stage of the previous preparation, the compound of formula (5) is coupled with the compound of formula (4), forming the compound of formula (6). This reaction is preferably carried out in a solvent such as acetonitrile, tetrahydrofuran, toluene, ethyl acetate, dichloromethane, dimethylformamide and the like or a mixture thereof, preferably using acetonitrile. The reaction can be carried out in the presence of a base such as

Triethylamine, potassium carbonate, diisopropylethylamine, pyridine and the like or a mixture thereof, and preferably using potassium carbonate. The reaction is carried out at a temperature of 25 to 70 ° C based on the choice of solvent and base. The duration of the reaction may range from 3 to 7 hours, preferably a period of 4 to 6 hours.

In the second stage of the previous preparation, the compound of formula (6) is subjected to deprotection followed by

Reductive cycloalkylation, forming the compound of formula (I). The deprotection reaction is preferably carried out in a solvent such as acetonitrile, tetrahydrofuran, toluene, ethyl acetate, dichloromethane, dimethylformamide, methanol, ethanol, isopropanol and the like or a mixture thereof, and preferably using an alcoholic solvent or dichloromethane. . The reaction can be carried out in the presence of an acid such as trifluoroacetic acid, sulfuric acid, acetic acid, perchloric acid, hydrochloric acid and the like or a mixture thereof.

20 themselves, and preferably using trifluoroacetic acid. The reaction is carried out at 25 to 60 ° C. The duration of the reaction may range from 4 to 10 hours, preferably a period of 4 to 8 hours. After deprotection, the isolated base is treated with a carbonyl compound such as acetone, cyclobutanone or cyclopentanone in the presence of a solvent such as tetrahydrofuran, acetic acid, dichloromethane, dichloroethane and the like or a mixture thereof, and preferably using dichloroethane. in the presence of acetic acid. The reaction is carried out in

Presence of a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, lithium aluminum hydride, sodium borohydride and the like or a mixture thereof, and preferably using sodium triacetoxyborohydride. The reaction is carried out at a temperature of 10 to 40 ° C. The duration of the reaction can range from 4 to 16 hours.

The compounds of formula (4) and formula (5) may be commercially available or may be prepared by conventional procedures or with modification, using known processes.

If necessary, any one or more of the following steps can be carried out:

5

10

fifteen

twenty

25

30

35

40

Four. Five

E11749555

09-24-2015

i) converting a compound of formula (I) into another compound of formula (I) or

ii) form a pharmaceutically acceptable salt.

The process (I) can be carried out by additional chemical modifications using well known reactions such as oxidation, reduction, protection, deprotection, transposition, halogenation, hydroxylation, alkylation, alkylthiolation, demethylation, O-alkylation, O-acylation, N-alkylation, N -alkenylation, N-acylation, N-cyanation, Nsulfonylation, coupling and the like.

In the process (ii), pharmaceutically acceptable salts can be prepared conventionally by reaction with the appropriate acid or acid derivative.

Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid and organic acids such as succinic, maleic, acetic, fumaric, citric, malic acids, tartaric, benzoic, p-toluic, p-toluenesulfonic, methanesulfonic or benzenesulfonic.

Examples

The novel compounds of the present invention were prepared according to the following experimental procedures, using appropriate materials and appropriate conditions.

Preparation I: Preparation of 4 - [(1-cyclobutyl-4-piperidinyl) oxy) aniline

Stage (i): Preparation of 1-cyclobutyl-4-piperidinol

A solution of 4-piperidinol (80 g, 0.792 mol) and cyclobutanone (67.2 g, 0.96 mol) in ethylene dichloride (1 L) was treated with sodium triacetoxyborohydride (251.1 g, 1,184 mol) in portions and the mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with chilled water (1 L) and the resulting mass was made alkaline with bleach solution. The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 500 ml). The combined organic phases were washed with water, dried over sodium sulfate and concentrated, yielding the title compound, 100 g (yield: 81.46%).

1H NMR (δ ppm): 1.55-2.02 (13H, m), 2.64-2.74 (2H, m), 3.68-3.70 (1H, m);

Mass (m / z): 155.9 (M + H) +.

Step (ii): Preparation of 1-cyclobutyl-4- (4-nitrophenoxy) piperidine

1-Cyclobutyl-4-piperidinol (80 g, 0.516 mol, obtained in the previous step) in dimethylformamide (300 ml) was added at 10 ° C under nitrogen to a stirred solution of sodium hydride (24.76 g, at 60% in mineral oil, 0.619 mol) in dimethylformamide (100 ml). The dough was stirred for 1 hour. A solution of 4fluoronitrobenzene (87.3 g, 0.619 mol) in dimethylformamide (300 ml) was added dropwise to the above reaction mass at room temperature. After completion of the reaction, the mass was quenched in cooled water (2 L) and stirred for 1 hour. The solids obtained were separated and dissolved in ethyl acetate (1 L). The resulting ethyl acetate phase was washed with water, dried over sodium sulfate and concentrated in vacuo. The residue thus obtained was purified by flash chromatography (methanol: chloroform, 2: 8), yielding the title compound, 99.7 g (yield: 70%).

1 H NMR (δ ppm): 1.67-1.71 (2H, m), 1.83-1.91 (4H, m), 2.00-2.08 (4H, m), 2.11 -2.19 (2H, m), 2.51-2.60 (2H, m), 2.71-2.78 (1H, m), 4.44-4.46 (1H, m), 6 , 93-6.95 (2H, d, J = 9.2 Hz), 8.17-8.20 (2H, d, J = 9.2 Hz);

Mass (m / z): 277.3 (M + H) +.

Step (iii): Preparation of 4 - [(1-cyclobutyl-4-piperidinyl) oxy) aniline

Hydrogen gas was bubbled through a solution of 1-cyclobutyl-4- (4-nitrophenoxy) piperidine (94.9 g, 0.344 mol, obtained in the previous step) on 10% Pd / C (95 g) in methanol (2 l) at room temperature for 5 hours. The mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo, yielding the title compound, 81 g (yield: 95.7%).

1 H NMR (δ ppm): 1.62-2.07 (12H, m), 2.62-2.76 (3H, m), 3.43-3.47 (2H, m), 4.13 -4.17 (1H, m), 6.61-6.63 (2H, d, J = 8.7 Hz), 6.75-6.77 (2H, d, J = 8.7 Hz);

Mass (m / z): 247.5 (M + H) +.

Preparation 2: Preparation of 4- (1-cyclobutylpiperidin-4-yloxy) benzylamine

Step (i): Preparation of 4- (4-cyanophenoxy) piperidine-1-carboxylic acid tert-butyl ester

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

E11749555

09-24-2015

A solution of 4-hydroxybenzonitrile (15 g, 0.126 mol), potassium carbonate (28.89 g, 0.208 mol) and tert-butyl ester of 4- (toluene-4-sulfonyloxy) piperidine-1 acid was stirred at 100 ° C -carboxylic acid (57.62 g, 0.162 mol) in dimethylformamide (150 ml) monitoring the progression of the reaction by thin layer chromatography. After completion of the reaction, the reaction mass was quenched with water (400 ml) and extracted with ethyl acetate (3 x 300 ml). The resulting ethyl acetate phase was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure, obtaining the crude residue which was further purified by flash chromatography using (ethyl acetate: hexane 1: 9), procuring the title compound, 21.25 g (yield: 55.8%).

1H NMR (δ ppm): 1.47 (9H, s), 1.74-1.80 (2H, m), 1.91-1.96 (2H, m), 3.33-3.40 (2H, m), 3.66-3.72 (2H, m), 4.53-4.57 (1H, m), 6.94-6.96 (2H, d, J = 8.78 Hz ), 7.57-7.59 (2H, d, J = 8.76 Hz);

Mass (m / z): 303.4 (M + H) +.

Step (ii): Preparation of 4- (1-cyclobutylpiperidin-4-yloxy) benzonitrile

Trifluoroacetic acid (81.4 g, 0.714 mol) was added to a stirred solution of 4- (4-cyanophenoxy) piperidine-1-carboxylic acid tert-butyl ester (21.25 g, 0.0704 mol) in dichloromethane (300 ml ) and the reaction mass was stirred overnight at room temperature. After completion of the reaction, the solvent was evaporated in vacuo and the residue thus obtained was alkalized with 10% caustic solution. The reaction mass was extracted with ethyl acetate twice, the combined organic phase was dried over sodium sulfate and evaporated under reduced pressure. The crude product thus obtained was treated with cyclobutanone (5.18 g, 0.074 mol), acetic acid (4.89 g, 0.0815 mol) in ethylene dichloride (100 ml) and stirred for 4 hours at room temperature. Sodium triacetoxyborohydride (35.06 g, 0.165 mol) was added to the reaction mass in a single batch and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and made alkaline with a solution of bleach. The phases were separated and the aqueous phase was extracted with dichloromethane twice. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and the residual mass was further purified by flash chromatography (dichloromethane: triethylamine, 9.5: 0.5), yielding the title compound, 10.92 g ( yield: 60.5%).

1 H NMR (δ ppm): 1.67-1.76 (2H, m), 1.88-1.97 (2H, m), 2.04-2.14 (6H, m) 2.49 ( 2H, sa), 2.64-2.68 (2H, m), 2,852.91 (1H, m), 4.47-4.49 (1H, m), 6.92-6.94 (2H, d, J = 8.8 Hz), 7.56-7.58 (2H, d, J = 8.8 Hz);

Mass (m / z): 257.4 (M + H) +.

Step (iii): Preparation of 4- (1-cyclobutylpiperidin-4-yloxy) benzylamine

A solution of 4- (1-cyclobutylpiperidin-4-yloxy) benzonitrile (8.22 g, 0.032 mol) in dry tetrahydrofuran (50 ml) was added to a stirred solution of lithium aluminum hydride (3.74 g, 0.098 mol) in dry tetrahydrofuran (30 ml) at 10 to 15 ° C under a nitrogen atmosphere. The resulting mass was further stirred for 20 minutes at room temperature and then heated to reflux for 4 hours. After completion of the reaction, the dough was cooled to 1015 ° C, quenched with water and made alkaline with a 4 N solution of sodium hydroxide. The reaction mass was filtered through Celite and the cake was washed with ethyl acetate. . The separated organic phase was dried over sodium sulfate and concentrated under reduced pressure, yielding the title compound, 7.17 g (yield: 86.2%).

1 H NMR (δ ppm): 1.65-1.72 (2H, m), 1.82-1.88 (4H, m), 1.96-2.05 (4H, m), 2.14 (2H, sa), 2.62 (2H, sa), 2.66-2.75 (1H, m), 3.79 (2H, m), 4.29-4.31 (1H, m), 6.85-6.88 (2H, d, J = 8.5 Hz), 7.20-7.21 (2H, d, J = 8.5 Hz);

Mass (m / z): 261.4 (M + H) +.

Preparation 3: Preparation of tert-butyl 4- [4- (2-chloroacetylamino) -3-fluorophenoxy) piperidino-1-carboxylate

Step (i): Preparation of tert-butyl 4- (3-fluoro-4-nitrophenoxy) piperidino-1-carboxylate

3-Fluoro-4-nitrophenol (5 g, 0.032 mol), potassium carbonate (6.34 g, 0.047 mol) and 4- (toluene-4sulfonyloxy) piperidine-1-carboxylic acid tert-butyl ester (1) 14 g, 0.04 mol) in dimethylformamide (50 ml). After completion of the reaction, the mass was quenched with water (100 ml) and extracted with ethyl acetate (2 x 100 ml). The resulting organic phase was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure, obtaining the crude residue which was further purified by flash chromatography using (ethyl acetate: hexane, 0.5: 9.5 ), procuring the title compound, 9.23 g (yield: 85%).

1H NMR (δ ppm): 1.47 (9H, s), 1.75-1.82 (2H, m), 1.94-1.99 (2H, m), 3.35-3.41 (2H, m), 3.67-3.73 (2H, m), 4.54-4.59 (1H, m), 6.72-6.77 (2H, m), 8.07-8.11 (1 H, m);

Mass (m / z): 341.3 (M + H) +.

Step (ii): Preparation of tert-butyl 4- (4-amino-3-fluorophenoxy) piperidino-1-carboxylate

Tert-Butyl 4- (3-fluoro-4-nitrophenoxy) piperidino-1-carboxylate (922 g, 0.027 mol) was hydrogenated over 10% Pd / C (9.22 g) in methanol (92.2 ml) bubbling hydrogen gas for 5 hours at room temperature. Leaked the

5

10

fifteen

twenty

25

30

35

40

Four. Five

E11749555

09-24-2015

mixture through a pad of Celite and the filtrate was concentrated in vacuo, yielding the title compound, 7.54 g (yield: 90%). The product was used as such in the next step without further purification.

1H NMR (δ ppm): 1.47 (9H, s), 1.75-1.82 (2H, m), 1.94-1.99 (2H, m), 3.35-3.41 (2H, m), 3.67-3.73 (2H, m), 4.54-4.59 (1H, m), 6.23-6.35 (3H, m);

Mass (m / z): 311.6 (M + H) +.

Step (iii): Preparation of tert-butyl 4- [4- (2-chloroacetylamino) -3-fluorophenoxy) piperidino-1-carboxylate

Tert-Butyl 4- (4-amino-3-fluorophenoxy) piperidino-1-carboxylate (7.54 g, 0.024 mol) was dissolved in dichloromethane (100 ml) and triethylamine (3.6 g, 0.036 mol) was added at room temperature. A solution of chloroacetyl chloride (2.9 g, 0.026 mol) in dichloromethane (15 ml) was added dropwise to the resulting mass at room temperature. After completion of the reaction, the organic mass was washed with water, dried over sodium sulfate and concentrated under reduced pressure, obtaining the crude residue which was further purified by flash chromatography using (ethyl acetate: hexane 1: 5), procuring the title compound, 5.94 g (yield: 64%).

1H NMR (δ ppm): 1.47 (9H, s), 1.72-1.76 (2H, m), 1.89-1.94 (2H, m), 3.31-3.37 (2H, m), 3.65-3.71 (2H, m), 4.21 (2H, s), 4.40-4.44 (1H, m), 6.70-6.74 (2H , m), 8.03-8.07 (1H, t, J = 8 Hz), 8.32 (1H, s);

Mass (m / z): 387.2 (M + H) +, 389.1 (M + H) +.

Example 1: Preparation of N- (4- (1-cyclobutylpiperidin-4-yloxy) phenyl) -2- (morpholin-4-yl) acetamide dihydrochloride

Step (i): Preparation of 2-chloro-N- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl) acetamide

Triethylamine (66.5 g, 0.688 mol) was added to a solution of 4 - [(1-cyclobutyl-4-piperidinyl) oxy] aniline (81 g, 0.329 mol, obtained in preparation 1) in dichloromethane (1 L) at 0 ° C under nitrogen atmosphere. The resulting mass was then treated dropwise with a solution of chloroacetyl chloride (44.6 g, 0.395 mol) in dichloromethane (1 L) at 0 ° C and stirred at 0 ° C for 1 hour. The reaction mixture was washed with water, dried over sodium sulfate, concentrated in vacuo and the crude compound thus obtained was purified by flash chromatography (methanol: chloroform, 2: 8), obtaining the title compound, 76.1 g (yield: 72%).

1 H NMR (δ ppm): 1.55-1.99 (12H, m), 2.49-2.67 (3H, m), 4.19 (2H, s), 4.26-4.28 (1H, m), 6.88-6.90 (2H, d, J = 8.9 Hz), 7.44-7.46 (2H, d, J = 8.9 Hz), 10.13 ( 1H, s);

Mass (m / z): 323.2 (M + H) +.

Step (ii): Preparation of N- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl) -2- (morpholin-4-yl) acetamide

A mixture of 2-chloro-N- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl] acetamide (76.0 g, 0.236, obtained in the previous step), morpholine (30, was stirred for 5 hours at reflux 8 g, 0.353 mol) and potassium carbonate (98 g, 0.71 mol) in acetonitrile (1.5 l). The mixture was partitioned between ethyl acetate (1 L) and water (1 L). The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 500 ml). The combined organic phases were washed with water twice, dried over sodium sulfate and concentrated in vacuo. The crude compound was purified by flash chromatography using (methanol: chloroform, 2: 8), yielding the title compound, 71 g (yield: 80%).

1 H NMR (δ ppm): 1.53-1.99 (12H, m), 2.46-2.68 (7H, m), 3.06 (2H, s), 3.60-3.63 (4H, m), 4.24-4.28 (1H, m), 6,856.88 (2H, d, J = 8.9 Hz), 7.47-7.50 (2H, d, J = 8 , 9 Hz), 9.5 (1H, s);

Mass (m / z): 374.2 (M + H) +.

Step (iii): Preparation of N- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl) -2- (morpholin-4-yl) acetamide dihydrochloride

A stirred solution of N- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl] -2- (morpholin-4-yl) acetamide (70 g, 0.187 mol) in diethyl ether (2.3 L) and methanol was treated (350 ml) with 31.5% w / v methanolic hydrochloric acid (54.36 ml, 0.469 mol). The reaction mass was stirred additionally 2-3 hours at room temperature. The solvent was decanted, the resulting solid mass was washed with ether (3 x 250 ml) and dried under reduced pressure, yielding the title compound, 70 g (yield: 83.9%).

IR (cm-1): 2983, 2934, 2499, 1688, 1604, 1553, 1509, 1243, 1234, 1120, 830;

1H NMR (δ ppm): 1.63-1.75 (2H, m), 1.89-2.01 (2H, m), 2.11-2.15 (4H, m), 2.34 -2.39 (2H, m), 2.80-2.90 (2H, m), 3.17-3.20 (2H, s), 3.21-3.26 (2H, m), 3 , 43-3.57 (2H, m), 3.69-3.73 (1H, m), 3.90-3.92 (2H, m), 4.15-4.16 (2H, m) , 4.20-4.22 (2H, m), 4.48-4.50 (1H, m), 6.97-7.03 (2H, m), 7.51-7.54 (2H, m), 10.57 (1H, sa), 10.78 (1H, sa), 11.11 (1H, sa);

Mass (m / z): 374.2 (M + H) +;

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

E11749555

09-24-2015

HPLC: 99.54%; P.F .: 249.2-251.5 ° C; salt content: 16.09% (as dihydrochloride).

Example 2: Preparation of 2- [4- (1-cyclobutylpiperidin-4-yloxy) phenylamino) -1- (morpholin-4yl) ethanone hydrochloride

Step (i): Preparation of 2- [4- (1-cyclobutylpiperidin-4-yloxy) phenylamino] -1- (morpholin-4-yl) ethanone

A mixture of 4- (1-cyclobutylpiperidin-4-yloxy) aniline (0.5 g, 0.002 mol), 2-chloro-1 (morpholin-4-yl) ethanone (0.5 g, was stirred at reflux temperature 0.003) and potassium carbonate (0.56 g, 0.004 mol) in dimethylformamide (25 ml). After completion of the reaction, the mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (250 ml) and water (250 ml). The combined organic phases were washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (chloroform: triethylamine, 9.5: 0.5), yielding the title compound, 0.3 g (yield: 40%).

Step (ii): Preparation of 2- [4- (1-cyclobutylpiperidin-4-yloxy) phenylamino) -1- (morpholin-4-yl) ethanone hydrochloride

A stirred solution of 2- [4- (1-cyclobutylpiperidin-4-yloxy) phenylamino] -1- (morpholin-4-yl) ethanone (0.3 g, 0.804 mmol) in diethyl ether (20 ml) was treated with hydrochloride 15% methanolic (0.23 ml, 0.965 mmol). The reaction mass was further stirred for 1 hour at room temperature. The solvent was decanted, the resulting solids were washed with ether (2 x 10 ml) and dried under reduced pressure, obtaining the title compound, 0.28 g (yield: 85%).

1H NMR (δ ppm): 1.65-1.75 (2H, m), 1.96-2.01 (2H, m), 2.08-2.17 (4H, m), 2.36 -2.37 (2H, m), 2.80-2.90 (2H, m), 3.15-3.19 (1H, m), 3.34-3.48 (5H, m), 3 , 55-3.67 (4H, m), 4.22-4.26 (3H, m), 4.45-4.48 (1H, m), 4.64-4.68 (1H, m) , 6.99-7.01 (2H, d, J = 8 Hz), 7.19-7.21 (2H, m), 11.15 (1H, sa);

Mass (m / z): 374.4 (M + H) +.

Example 3: Preparation of N- [4- (1-cyclobutylpiperidin-4-yloxy) -2-fluorophenyl) -2- (morpholin-4yl) acetamide dihydrochloride

Step (i): Preparation of tert-butyl 4- [3-fluoro-4- (2- (morpholin-4-yl) acetylamino) phenoxy) piperidino-1-carboxylate

A mixture of tert-butyl 4- [4- (2-chloroacetylamino) -3-fluorophenoxy] piperidine-1-carboxylate was stirred for 5 hours at reflux (3.31 g, 0.0085 mol, obtained in preparation 3 ), morpholine (0.89 g, 0.01 mol) and potassium carbonate (1.75 g, 0.012 mol) in acetonitrile (30 ml). The mixture was concentrated under reduced pressure and the residue thus obtained was partitioned between ethyl acetate (50 ml) and water (50 ml). The resulting aqueous phase was extracted with ethyl acetate (2 x 50 ml). The combined organic phases were washed with brine solution, dried over sodium sulfate and concentrated. The crude compound was purified by flash chromatography (ethyl acetate: hexane, 3: 7), yielding the title compound, 3.1 g (yield: 83.5%).

1H NMR (δ ppm): 1.47 (9H, s), 1.71-1.75 (2H, m), 1.89-1.92 (2H, m), 2.62-2.64 (4H, t, J = 4 Hz), 3.16 (2H, s), 3.303.36 (2H, m), 3.65-3.71 (2H, m), 3.77-3.79 ( 4H, t, J = 4 Hz), 4.39-4.42 (1H, m), 6.69-6.71 (2H, d, J = 8 Hz), 8.14-8.18 (1H , t, J = 8 Hz), 9.27 (1H, s);

Mass (m / z): 438.2 (M + H) +.

Step (ii): Preparation of N- [4- (1-cyclobutylpiperidin-4-yloxy) -2-fluorophenyl) -2- (morpholin-4-yl) acetamide

Trifluoroacetic acid (8.1 g, 0.071mol) was added to a stirred solution of tert-butyl 4- [3-fluoro-4- (2- (morpholin-4yl) acetylamino) phenoxy] piperidino-1-carboxylate (3 , 1 g, 0.007 mol, obtained in the previous step) in dichloromethane (25 ml), and the reaction mass was stirred overnight at room temperature. After completion of the reaction, the solvent was evaporated in vacuo and the residue thus obtained was alkalized with 10% caustic solution. The reaction mass was extracted with ethyl acetate twice, the combined organic phase was dried over sodium sulfate and evaporated under reduced pressure. The crude product thus obtained was treated with cyclobutanone (0.6 g, 0.008 mol) in ethylene dichloride (30 ml) and stirred for 4 hours at room temperature. Sodium triacetoxyborohydride (3 g, 0.014 mol) was added to the reaction mass in a single batch and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and made alkaline with a solution of bleach. The phases were separated and the aqueous phase was extracted with dichloromethane twice. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and the residual mass was further purified by flash chromatography (dichloromethane: triethylamine, 9.5: 0.5), yielding the title compound, 1.52 g ( yield: 55%).

1H NMR (δ ppm): 1.64-1.68 (3H, m), 1.70-1.73 (2H, m), 1.82-1.91 (4H, m), 1.96 -2.05 (4H, m), 2.14-2.15 (2H, m), 2.62-2.64 (4H, m), 3.16 (2H, s), 3.77-3 , 79 (4H, t, J = 4.0 Hz), 4.25-4.26 (1H, m), 6.68-6.70 (2H, m), 8.12-8.16 (1H , t, J = 8.0 Hz), 9.20 (1H, sa);

Mass (m / z): 392.2 (M + H) +. 12

image11

Step (iii): Preparation of N- [4- (1-cyclobutylpiperidin-4-yloxy) -2-fluorophenyl) -2- (morpholin-4yl) acetamide dihydrochloride

Methanolic hydrochloride (2.08 ml, 0.009 mol, 15% w / v) was added to a stirred solution of N- [4- (1-cyclobutylpiperidin4-yloxy) -2-fluorophenyl] -2- (morpholin-4-yl ) acetamide (1.52 g, 0.004 mol) in diethyl ether (5 vol.) and the stirring was further stirred

5 reaction mass for 2-3 hours at room temperature. The solvent was decanted, the resulting solids were washed with ether (2 x 10 ml) and dried under reduced pressure, obtaining the title compound, 1.6 g (yield: 86.2%).

1 H NMR (δ ppm): 1.63-1.72 (2H, m), 1.92-2.02 (2H, m), 2.13-2.21 (4H, m), 2.35 -2.36 (3H, m), 2.80-2.89 (2H, m), 3.15-3.26 (4H, m), 3.56-3.70 (2H, m), 3 , 77-3.80 (2H, m), 3.90-3.91 (2H, m), 3.93-4.21 (2H, m), 4.55-4.76 (1H, m) ,

10 6.83-6.89 (1H, m), 7.04-7.07 (1H, m), 7.58-7.60 (1H, m), 10.39 (1H, sa), 10 , 55 (1H, sa), 11.05 (1H, sa);

Mass (m / z): 392.2 (M + H) +.

Example 4: Preparation of N- [4- (1-cyclobutylpiperidin-4-yloxy) benzyl] morpholin-4-ylamide

A solution of morpholino-4-carbonyl chloride (0.45 g, 0.003 mol), 4- (1-cyclobutylpiperidin-4-yloxy) benzylamine (0.5 g, 0.002 mol, obtained in preparation 2) was stirred at room temperature and triethylamine (0.4 g, 0.004 mol)

15 in dichloromethane (20 ml). After the reaction was over, the reaction mass was quenched with water and extracted with dichloromethane. The combined organic phase was dried over sodium sulfate and concentrated under reduced pressure, obtaining the crude compound that was further purified by flash chromatography (ethyl acetate: methanol, 98: 2), yielding the title compound, 0.45 g (yield: 60%).

1 H NMR (δ ppm): 1.66-1.78 (2H, m), 1.75-1.78 (2H, m), 2.07-2.19 (6H, m), 2.59 (2H, sa), 2.67-2.69 (2H, m), 2.93

20 2.97 (1H, m), 3.34-3.36 (4H, t, J = 4.8), 3.67-3.69 (4H, t, J = 4.5), 4, 35-4.36 (2H, d, J = 5.14), 4.41 (1H, sa), 4.66 (1H, sa), 6.84-6.86 (2H, d, J = 8 , 4), 7.21-7.23 (2H, d, J = 8.4);

Mass (m / z): 374.3 (M + H) +.

Examples 5-39

The compounds of Examples 5-39 were prepared following the procedures described in Examples 25 1 to 4 with some non-critical variations.

5.

N- [4- (1-Cyclobutylpiperidin-4-yloxy) 3-fluorophenyl] -2- (morpholin-4yl) acetamide 1H NMR (δ ppm): 1.42-1.87 (6H, m), 1.97-2.05 (8H, m), 2.61-2.63 (4H, t, J = 4, 4 Hz), 2.78-2.8 (1H, m), 3.13 (2H, s), 3.76-3.79 (4H, t, J = 4.4 Hz), 4.02 ( 1H, m), 6.93-6.98 (1H, t, J = 8.8 Hz), 7.11-7.14 (1H, d, J = 8.6 Hz), 7.49-7 , 52 (1H, dd, J = 14.9, 2.4 Hz), 8.99 (1H, sa); Mass (m / z): 392 (M + H) +.

6.

N- [4- (1-Cyclobutylpiperidin-4-yloxy) 2-methylphenyl] -2- (3,3difluoropyrrolidin-1-yl) acetamide 1 H NMR (δ ppm): 1.68-182 (6H, m), 2.01-2.05 (4H, m), 2.0-2.1 (2H, m), 2.22 (3H , s), 2.34-2.4 (2H, m), 2.5-2.61 (2H, m), 2.71-2.73 (1H, m), 2,973.01 (2H, t ), 3.07-3.13 (2H, t, J = 4.0 Hz), 3.33 (2H, s), 4.28 (1H, m), 6.766.77 (2H, m), 7 , 77-7.79 (1H, m), 8.75 (1H, sa); Mass (m / z): 408 (M + H) +.

7.

N- [4- (1-Cyclobutylpiperidin-4-yloxy) 2-trifluoromethylphenyl] -2- (piperidin-1yl) acetamide 1 H NMR (δ ppm): 1.42-1.47 (2H, m), 1.62-1.67 (4H, m), 1.72-1.79 (2H, m), 1.78 -1.8 (2H, m), 2.0-2.05 (6H, m), 2.25-2.35 (2H, m), 2.37-2.55 (4H, m), 2 , 6-2.64 (2H, m), 2.83-2.86 (1H, m), 3.08 (2H, s), 4.36-4.38 (1H, m), 7.057.08 (1H, dd, J = 9, 2.6 Hz), 7.13-7.14 (1H, d, J = 2.7 Hz), 8.22-8.24 (1H, d, J = 9 Hz), 9.85 (1H, sa); Mass (m / z): 440 (M + H) +

8.

N- [1- (Cyclopentylpiperidin-4-yloxy) phenyl] -2- (morpholin-4-yl) acetamide 1 H NMR (δ ppm): 1.45-1.56 (4H, m), 1.69-1.71 (2H, m), 1.86-1.90 (4H, m), 2.03 -2.08 (2H, m), 2.41-2.45 (2H, m), 2.61-2.63 (4H, t, J = 4.46 Hz), 2,802.83 (2H, m ), 3.13 (2H, s), 3.58-3.61 (1H, m), 3.76-3.78 (4H, t, J = 4.5 Hz), 4.13-4, 31 (1H, m), 6.87-6.9 (2H, d, J = 8.8 Hz), 7.44-7.46 (2H, d, J = 8.8 Hz), 8.93 (1H, sa); Mass (m / z): 388 (M + H) +.

9.

N- [4- (1-Cyclobutylpiperidin-4-ioxy) 2-trifluoromethylphenyl] -2- (morpholin-4yl) acetamide 1 H NMR (δ ppm): 1.68-1.73 (2H, m), 1.80-1.90 (4H, m), 1.97-2.06 (4H, m), 2.14 -2.18 (2H, m), 2.63-2.65 (6H, m), 2.73-2.75 (1H, m), 3.15 (2H, s), 3.76-3 , 78 (4H, m), 4.32 (1H, m), 7.06-7.09 (1H, m), 7.14 (1H, d, J = 2.59 Hz), 8.19- 8.21 (1H, d, J = 8.9 Hz), 9.65 (1H, sa); Mass (m / z): 442 (M + H) +.

E11749555

09-24-2015 E11749555

10.

N- [4- (1-Isopropylpiperidin-4-yloxy) 2-methylphenyl] -2- (pyrrolidin-1yl) acetamide 1H NMR (δ ppm): 1.26-1.28 (6H, d), 1.84-1.87 (4H, m), 2.23 (3H, s), 2,702.73 (4H, m ), 2.39 (2H, m), 2.87-2.89 (2H, m), 2.94-3.01 (5H, m), 3.49 (2H, s), 4.42- 4.45 (1H, m), 6.47-6.77 (2H, m), 7.81-7.83 (1H, d, J = 9.2 Hz), 9.08 (1H, sa) ; Mass (m / z): 360.3 (M + H) +.

eleven.

N- [4- (1-Cyclobutylpiperidin-4-yloxy) 2-methylphenyl] -2- (pyrrolidin-1yl) acetamide 1H NMR (δ ppm): 1.64-1.74 (5H, m), 1.85-1.86 (2H, m), 1.87-1.90 (3H, m), 2.06 -2.22 (4H, m), 2.22-2.27 (5H, m), 2.60-2.62 (2H, m), 2.72-2.77 (5H, m), 3 , 31 (2H, s), 4.25-4.29 (1H, m), 6.75-6.77 (2H, m), 7.79-7.81 (1H, d, J = 8, 0 Hz), 9.05 (1H, sa); Mass (m / z): 372 (M + H) +.

12.

N- [4- (1-Cyclopentylpiperidin-4-yloxy) -2-methylphenyl] -2- (piperidin-1yl) acetamide 1H NMR (δ ppm): 0.86-0.9 (2H, m), 1.54-1.72 (8H, m), 1.85-1.87 (4H, m), 2.0 -2.03 (3H, m), 2.23 (3H, s), 2.24-2.26 (2H, m), 2.35-2.65 (6H, m), 2,782.80 (2H , m), 3.10 (2H, s), 4.12-4.28 (1H, m), 6.76-6.78 (2H, m), 7.9-7.92 (1H, d , J = 8.8 Hz), 9.23 (1H, sa); Mass (m / z): 400 (M + H) +.

13.

N- [4- (1-Cyclobutylpiperidin-4-yloxy) 2-methylphenyl] -2- (piperidin-1yl) acetamide 1H NMR (δ ppm): 0.86-0.9 (2H, m), 1.49-1.50 (2H, m), 1.61-2.01 (12H, m), 2.15 -2.17 (2H, m), 2.25 (3H, s), 2.55-2.57 (6H, m), 2.67-2.77 (1H, m), 3.10 (2H , s), 4.10-4.28 (1H, m), 6.75-6.78 (2H, m), 7.89-7.91 (1H, d, J = 8.8 Hz), 9.23 (1H, sa); Mass (m / z): 386 (M + H) +.

14.

N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -N-methyl-2- (morpholin-4yl) acetamide 1H NMR (δ ppm): 1.67-1.74 (3H, m), 2.02-2.05 (7H, m), 2.19-2.21 (2H, m), 2.38 -2.4 (3H, m), 2.63-2.65 (2H, m), 2.75-2.84 (2H, m), 2.90 (2H, s), 3.22 (3H , s), 3.68-3.70 (4H, m), 4.30-4.34 (1H, m), 6.90-6.92 (2H, d, J = 8 Hz), 7, 08-7.10 (2H, m); Mass (m / z): 388 (M + H) +.

fifteen.

N- [4- (1-Cyclopentylpiperidin-4-yloxy) -2-methylphenyl] -2- (R-2-methylpyrrolidin-1-yl) acetamide 1 H NMR (δ ppm): 1.13-1.15 (3H, d, J = 6.0 Hz), 1.42-1.46 (2H, m), 1,541.57 (4H, m), 1.69-1.69 (2H, m), 1.78-1.86 (6H, m), 1.97-2.02 (2H, m), 2.22 (3H, s), 2, 31-2.34 (2H, m), 2.39-2.44 (1H, m), 2.52-2.67 (2H, m), 2.72.79 (2H, m), 3, 06-3.1 (1H, d, J = 16.9 Hz), 3.21-3.25 (1H, m), 3.45-3.49 (1H, d, J = 16.9 Hz) , 4.23-4.27 (1H, m), 6.76-6.88 (2H, m), 7.84-6.86 (1H, d, J = 8.5 Hz), 9.21 (1H, sa); Mass (m / z): 400 (M + H) +.

16.

N- [4- (1-Cyclobutylpiperidin-4-yloxy) 2-methylphenyl] -2- (R-2-methylpyrrolidin1-yl) acetamide 1H NMR (δ ppm): 1.13-1.14 (4H, d, J = 6.0 Hz), 1.67-1.82 (6H, m), 1,892.06 (10H, m), 2.1-2.15 (2H, m), 2.22 (3H, s), 2.43-2.63 (2H, m), 3.06-3.1 (1H, d, J = 16 , 9 Hz), 3.20-3.23 (1H, m), 3.44-3.49 (1H, d, J = 16.9 Hz), 4.22-4.27 (1H, m) , 6.75-6.78 (2H, m), 7.83-6.86 (1H, d, J = 8.7 Hz), 9.21 (1H, sa); Mass (m / z): 386 (M + H) +.

17.

N- [4- (1-Cyclobutylpiperidin-4-yloxy) 2-methoxyphenyl] -2- (morpholin-4yl) acetamide 1 H NMR (δ ppm): 1.65-1.78 (2H, m), 1.91-1.94 (2H, m), 2.08-2.17 (6H, m), 2.51 -2.54 (2H, m), 2.62-2.64 (4H, t), 2.70-2.72 (2H, m), 2.92-2.96 (1H, m), 3 , 14 (2H, s), 3.77-3.85 (4H, t), 3.88 (3H, s), 4.3-4.39 (1H, m), 6.46-6.49 (2H, m), 8.20-8.22 (1H, d, J = 9.2 Hz), 9.54 (1H, sa); Mass (m / z): 404 (M + H) +.

18.

N- [4- (1-Cyclobutylpiperidin-4-yloxy) 2-trifluoromethylphenyl] -2- (4-hydroxypiperidin-1-yl) acetamide 1 H NMR (δ ppm): 1.6-1.73 (9H, m), 2.02-2.06 (6H, m), 2.17-2.19 (2H, m), 2.42 -2.46 (2H, m), 2.58-2.61 (2H, m), 2.74-2.77 (1H, m), 2.84-2.87 (2H, m), 3 , 14 (2H, s), 3.79 (1H, m), 4.30-4.33 (1H, m), 7.06-7.09 (1H, dd, J = 12.0, 2, 4 Hz), 7.14-7.15 (1H, d, J = 2.8 Hz), 8.22-8.23 (1H, d, J = 12 Hz), 9.74 (1H, sa) ; Mass (m / z): 456 (M + H) +.

19.

N- [4- (1-Cyclobutylpiperidin-1-yloxy) phenyl] -2- (4-hydroxypiperidin-1yl) acetamide 1 H-NMR (δ ppm): 1.66-1.76 (4H, m), 1.87-1.97 (4H, m), 2.03-2.05 (6H, m), 2.38 -2.43 (4H, m), 2.64-2.65 (2H, m), 2.86-2.95 (4H, m), 3.11 (2H, s), 3.77-3 , 80 (1H, m), 4.30-4.33 (1H, m), 6.86-6.89 (2H, dd), 7.44-7.46 (2H, dd), 9.04 (1H, sa); Mass (m / z): 388 (M + H) +.

twenty.

N- [4- (1-Cyclopentylpiperidin-4-yloxy) -2fluorophenyl] -2- (morpholin-4-yl) acetamide dihydrochloride 1 H-NMR (δ ppm): 1.53-1.55 (2H, m), 1.73-1.79 (4H, m), 2.01-2.04 (5H, m), 2.09 -2.21 (2H, m), 3.04-3.07 (2H, m), 3.20-3.37 (4H, m), 3.52-3.55 (2H, m), 3 , 80-3.97 (4H, m), 4.23 (2H, m), 4.58-4.60 (1H, m), 6.85-6.94 (1H, m), 7.05 -7.11 (1H, m), 7.59-7.63 (1H, m), 10.4 (1H, sa), 10.5 (1H, sa), 10.67 (1H, sa); Mass (m / z): 406.2 (M + H) +.

twenty-one.

N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (pyrrolidin-1yl) acetamide 1H NMR (δ ppm): 1.65-1.72 (4H, m), 1.72-1.87 (8H, m), 2.03-2.14 (2H, m), 2.62 -2.65 (2H, m), 2.69-2.75 (7H, m), 3.26 (2H, s), 4.25-4.27 (1H, m), 6.87-6 , 89 (2H, dd), 7.45-7.47 (2H, dd), 8.97 (1H, sa); Mass (m / z): 358 (M + H) +.

09-24-2015 E11749555

22

N- [4- (1-Isopropylpiperidin-4-yloxy) phenyl] -2- (morpholin-4-yl) acetamide 1H NMR (δ ppm): 1.06-1.08 (6H, d, J = 6.48 Hz), 1.63 (2H, m), 1.80-1.84 (2H, m), 2.01-2.02 (2H, m), 2.40 (2H, m), 2.61-2.64 (4H, t, J = 4.5 Hz), 3.13 (2H, s) , 4.35 (1H, m), 3.77-3.79 (4H, t, J = 4.5 Hz), 4.26-4.27 (1H, m), 6.886.90 (2H, d , J = 8.8 Hz), 7.44-7.46 (2H, d, J = 8.8 Hz), 8.92 (1H, sa); Mass (m / z): 362.3 (M + H) +.

2. 3.

N- [4- (1-Cyclopropylpiperidin-4-yloxy) phenyl] -2- (morpholin-4yl) acetamide 1H NMR (δ ppm): 0.76-0.78 (2H, m), 1.13 (2H, m), 1.93-1.99 (2H, m), 2.16-2.19 (2H, m), 3.33-3.39 (6H, m), 3.42-3.44 (3H, m), 3.76-3.77 (2H, m), 3.80-3 , 83 (2H, m), 4.18 (2H, m), 4.51 (1H, m), 6.97-6.05 (2H, dd), 7.52-7.56 (2H, dd ), 8.92 (1H, sa); Mass (m / z): 360.3 (M + H) +.

24.

N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (4-isopropyl [1,4diazepan-1-yl) acetamide 1 H NMR (δ ppm): 1.17-1.19 (6H, d, J = 6.54 Hz), 1.61-1.63 (3H, m), 1,901.98 (8H, m), 2.30-2.35 (2H, m), 2.49-2.55 (2H, m), 2.70-2.72 (2H, m), 2.91-2.94 (2H, m ), 3.01-3.07 (4H, m), 3.15-3.19 (5H, m), 4.30-4.33 (1H, m), 6.88-6.99 (2H , dd, J = 8.9 Hz), 7.49-7.51 (2H, dd, J = 8.8 Hz), 8.95 (1H, sa); Mass (m / z): 429.1 (M + H) +.

25.

N- [4- (1-Cyclobutylpiperidine-4-yloxy) phenyl] -2- (2-hydroxymethylmorpholin-4-yl) acetamide 1H NMR (δ ppm): 1.68-1.72 (3H, m), 1.89-1.97 (3H, m), 2.13-2.19 (5H, m), 2.33 -2.36 (2H, m), 2.80-2.86 (3H, m), 3.07-3.10 (1H, m), 3.17-3.20 (3H, m), 3 , 69-3.72 (1H, m), 3.82-3.85 (2H, m), 3.99-4.01 (1H, m), 4.03 (1H, m), 4.48 -4.51 (1H, m), 4.70 (1H, m), 6.97-7.03 (2H, dd), 7.51-7.54 (2H, dd), 8.83 (1H , sa); Mass (m / z): 404.5 (M + H) +.

26.

N- [4- (1-Cyclobutylpiperidin-1-yloxy) phenyl] -3- (morpholin-4yl) propionamide 1H NMR (δ ppm): 1.63-1.68 (3H, m), 1.83-1.87 (1H, m), 1.97-2.02 (3H, m), 2.13 -2.16 (3H, m), 2.30-2.35 (3H, m), 2.78-2.89 (4H, m), 3.06-3.09 (3H, m), 3 , 17-3.20 (2H, m), 3.58-3.61 (3H, m), 3.94-3.97 (2H, m), 4.67 (1H, m), 6.92 -6.99 (2H, dd, J = 8.8 Hz), 7.49-7.51 (2H, dd, J = 8.8 Hz), 8.85 (1H, sa); Mass (m / z): 388.2 (M + H) +.

27.

N- [4- (1-Cyclopentylpiperidin-4-yloxy) phenyl] -2 (piperidin-1-yl) acetamide dihydrochloride 1 H NMR (δ ppm): 1.17-1.23 (2H, m), 1.31-1.32 (2H, m), 1.71-1.72 (9H, m), 1.74 -1.77 (4H, m), 1.98-2.01 (2H, m), 3.01-3.06 (4H, m), 3.38-3.40 (4H, m), 4 , 06-4.07 (2H, m), 4.50-4.52 (1H, m), 6.97-7.03 (2H, m), 7.50-7.54 (2H, m) , 9.7 (1H, sa), 10.48 (1H, sa), 10.48 (1H, sa); Mass (m / z): 386.5 (M + H) +.

28.

N- [4- (1-Cyclopentylpiperidin-4-yloxy) phenyl] -2 (pyrrolidin-1-yl) acetamide dihydrochloride 1H NMR (δ ppm): 1.52-1.60 (3H, m), 1.71-1.75 (2H, m), 1.80-1.81 (3H, m), 1.98 -2.00 (8H, m), 2.97-3.11 (6H, m), 3.58-3.60 (3H, m), 4.21 (2H, s), 4.49-4 , 54 (1H, m), 6.96-7.03 (2H, dd, J = 8.0 Hz), 7.52-7.52 (2H, dd, J = 8 Hz), 8.86 ( 1H, sa), 10.31 (1H, sa), 10.77 (1H, sa), 10.99 (1H, sa); Mass (m / z): 372.1 (M + H) +.

29.

N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (piperidin-1yl) acetamide 1 H NMR (δ ppm): 1.68-1.73 (2H, m), 1.77-1.90 (4H, m), 2.01-2.13 (2H, m), 2.15 -2.19 (4H, m), 2.33-2.37 (2H, m), 2.83-2.90 (2H, m), 3.01-3.03 (2H, m), 3 , 04-3.06 (2H, m), 3.17-3.20 (2H, m), 3.34-3.39 (2H, m), 3.57-3.70 (1H, m) , 4.07 (2H, s), 4.48-4.50 (1H, m), 6.97-7.03 (2H, dd, J = 12.0 Hz), 7.51-7.54 (2H, dd, J = 12.0 Hz), 8.93 (1H, sa); Mass (mlz): 372.4 (M + H) +.

30

N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2trifluoromethylphenyl] -2- (pyrrolidin-1yl) acetamide dihydrochloride 1H NMR (δ ppm): 1.68-1.73 (3H, m), 1.88-1.90 (3H, m), 2.02-2.03 (5H, m), 2.39 -2.40 (2H, m), 2.91-2.99 (2H, m), 3.06-3.10 (2H, m), 3.15-3.38 (2H, m), 3 , 55-3.58 (2H, m), 3.74-3.85 (2H, m), 4.23 (2H, s), 4.70-4.71 (1H, m), 7.31 -7.33 (1H, d, J = 8.0 Hz), 7.36-7.42 (2H, m), 9.51 (1H, sa), 10.29 (1H, sa), 10, 36 (1H, sa), 11.35 (1H, sa); Mass (mlz): 426.1 (M + H) +.

31.

N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -N- (2-morpholin-4-ethyl) acetamide 1 H NMR (δ ppm): 1.66-1.75 (7H, m), 1.87-1.88 (2H, m), 2.05-2.09 (6H, m), 2.43 -2.48 (7H, m), 2.67 (2H, sa), 3.65-3.67 (4H, t, J = 4.4 Hz), 3.78-3.81 (2H, t ), 4.4 (1H, m), 6.89-6.91 (2H, d, J = 8.7 Hz), 7.10-7.13 (2H, d, J = 8.7 Hz) ; Mass (mlz): 402.4 (M + H) +.

32

[4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] - (2-morpholin-4-ethyl) amine 1 H NMR (δ ppm): 1.64-1.72 (2H, m), 1.77-1.93 (6H, m), 2.02-2.05 (2H, m), 2.07 -2.08 (2H, m), 2.47-2.5 (4H, m), 2.61-2.63 (4H, m), 2.70-2.74 (1H, m), 3 , 11-3.13 (2H, t), 3.71-3.73 (4H, t), 4.10 (1H, m), 6.57-6.60 (2H, d, J = 8, 7 Hz), 6.79-6.82 (2H, d, J = 8.7 Hz); Mass (mlz): 360.4 (M + H) +.

09-24-2015

33.

L (+) - N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2 (R-2-hydroxymethylpyrrolidin-1-yl) acetamide tartrate 1H NMR (δ ppm): 1.81-1.91 (5H, m), 2.05-2.16 (5H, m), 2.30-2.35 (4H, m), 2.72 -2.74 (1H, m), 3.05-3.17 (4H, m), 3.31-3.35 (2H, m), 3.43-3.47 (1H, m), 3 , 62-3.71 (3H, m), 3.83-3.87 (1H, m), 4.40 (2H, s), 4.63-4.66 (1H, m), 6.97 -6.99 (2H, dd, J = 8.2, 2.04 Hz), 7.51-7.53 (2H, dd, J = 8.2, 2.00 Hz); Mass (m / z): 388.3 (M + H) +.

3. 4.

N- [2- (1-Cyclobutylpiperidin-4-yloxy) pyridin-4-yloxy) pyridin-5-yl] -N [2- (morpholin-4-yl) ethyl] acetamide 1H NMR (δ ppm): 1.66-1.73 (6H, m), 1.89 (2H, m), 1.97-2.18 (6H, m), 2.42-2.48 (6H, m), 2.76 (2H, sa), 2.98-3.03 (2H, m), 3.60-3.66 (4H, m), 3.77-3.80 (2H , t), 4.55 (1H, m), 6.74-6.76 (1H, d, J = 8.6 Hz), 7.46-7.48 (1H, dd, J = 8.6 , 2.6 Hz), 8.01-8.02 (1H, d, J = 2.4 Hz); Mass (mlz): 403.3 (M + H) +.

35

N- [2- (1-Cyclobutylpiperidin-4-yloxy) pyridin-5-yl] -2- (piperidin-1yl) acetamide 1 H NMR (δ ppm): 1.63-1.66 (8H, m), 1.81-1.83 (3H, m), 2.03-2.06 (6H, m), 2.18 -2.13 (4H, m), 2.54-2.55 (4H, m), 3.08 (2H, s), 5.03 (1H, m), 6.70-6.72 (1H , d, J = 8.8 Hz), 7.92-7.95 (1H, dd, J = 8.8, 2.6 Hz), 8.18-8.19 (1H, d, J = 2 , 6 Hz), 9.15 (1H, sa); Mass (m / z): 373.3 (M + H) +.

36.

N- [2- (1-Cyclobutylpiperidin-4-yloxy) pyridin-5-yl] -2- (morpholin-4-yl) acetamide 1 H NMR (δ ppm): 1.51-1.95 (12H, m), 2.43-2.65 (7H, m), 3.06 (2H, s), 3.60-3.79 (4H, m), 5.22 (1H, m), 6.70-6.73 (1H, d, J = 8.8 Hz), 7.98-8.00 (1H, dd, J = 8 , 5 Hz, 2.4 Hz), 8.16-8.18 (1H, d, J = 2.4 Hz), 8.97 (1H, sa); Mass (m / z): 375.4 (M + H) +.

37

N- [4- (1-Cyclobutylpiperidin-4-yloxy) 2-fluorophenyl] -N- [2- (morpholin4yl) ethyl] acetamide 1H NMR (δ ppm): 1.63-1.76 (7H, m), 1.85-1.89 (2H, m), 2.05-2.09 (6H, m), 2.43 -2.48 (7H, m), 2.67 (2H, sa), 3.65-3.67 (4H, t, J = 4.4 Hz), 3.78-3.81 (2H, t ), 4.4 (1H, m), 6.89-6.91 (2H, m), 7.10-7.8 (1H, m); Mass (m / z): 420.4 (M + H) +.

38.

L - (+) - N- [4- (1-Cyclopropylpiperidin-4-yloxy) phenyl] -N [2- (morpholin-4-yl) ethyl] acetamide tartrate 1H NMR (δ ppm): 0.81-0.85 (4H, m), 1.83 (3H, s), 1.90-2.02 (2H, m), 2.102.2 (2H, m ), 2.40-2.50 (1H, m), 2.66-2.69 (6H, m), 3.18-3.22 (2H, m), 3,363.39 (2H, m), 3.70-3.73 (4H, m), 3.86-3.90 (2H, m), 4.60-4.70 (1H, m), 7.07-7.09 (2H, d , J = 8.7 Hz), 7.26-7.28 (2H, d, J = 8.7 Hz); Mass (m / z): 388.4 (M + H) +.

39.

N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (1-acetylpiperazin-4yl) acetamide 1H NMR (δ ppm): 1.69-1.74 (3H, m), 1.76-1.80 (3H, m), 2.01-2.10 (4H, m), 2.12 (3H, s), 2.59-2.64 (8H, m), 2.75-2.80 (1H, m), 3.17 (2H, s), 3.53-3.56 (2H , m), 3.6-3.65 (2H, m), 4.3-4.4 (1H, m), 6.88-6.9 (2H, d, J = 8.88 Hz), 7.44-7.46 (2H, d, J = 8.84 Hz), 8.8 (1H, sa); Mass (m / z): 415.2 (M + H) +.

Examples 40-51:

The person skilled in the art can prepare the compounds of examples 40-51 following the procedures described above.

40

N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-methylphenyl] -2- (4-hydroxypiperidin-1-yl) acetamide

41.

N- [4- (1-Cyclopropylpiperidin-4-yloxy) phenyl] -2- (R-2-hydroxymethylpyrrolidin-1-yl) acetamide

42

N- [4- (1-Cyclobutylpiperidin-4-yloxy) benzyl] -2- (morpholin-4-yl) acetamide

43

N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-fluorobenzyl] -2- (morpholin-4-yl) acetamide

44.

N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (3-hydroxyazetidin-1-yl) acetamide

Four. Five.

N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-fluorophenyl] -2- (3-methoxyazetidin-1-yl) acetamide

46.

N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-fluorophenyl] -2- (2-hydroxymethylpyrrolidin-1-yl) acetamide

47

N- [2-Chloro-4- (1-cyclobutylpiperidin-4-yloxy) phenyl] -2- (morpholin-4-yl) acetamide

48.

N- [2-Chloro-4- (1-cyclobutylpiperidin-4-yloxy) phenyl] -2- (piperidin-1-yl) acetamide

49.

N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (tetrahydropyran-4-yloxy) acetamide

fifty.

2- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-fluorophenylamino] -1- (morpholin-4-yl) ethanone

51.

N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-fluorophenyl] -N- (2-morpholin-4-ylethyl) acetamide

image12

Biological assays Example 52: Binding and functional assays for human or rat histamine H3 receptor

The compounds can be evaluated according to the following procedures.

5 Materials and procedure: Receptor source: Frontal cortex of rat brain or recombinant human cDNA expressed in CHO cells Radioligand: [3H] R--methylhistamine Final ligand concentration - [3.0 nM) Non-specific determinant: R- -methylhistamine (100 uM)

10 Reference compound: R--methylhistamine Positive control: R--methylhistamine

Incubation conditions:

Increasing concentrations of test compounds or standards were incubated with membrane receptors and radioligand in 5 mM MgCl 2 and 50 mM TRIS-HCl (pH 7.4) for 60 minutes at room temperature. The

15 reaction by rapid vacuum filtration in fiberglass filters. The radioactivity trapped in the filters was determined and compared with the control values to assess any interaction of the test compound or compounds with the human receptor or cloned rat binding site.

Example number

Ki (nM)

one

8.7

2

6.4

3

14.9

7

14.8

10

8.4

eleven

1.9

12

7.5

13

3.3

14

4.9

fifteen

4

16

2.4

19

6.4

twenty-one

1.1

22

8.3

24

1.0

25

4.05

26

6.7

27

4.1

28

3.8

E11749555

09-24-2015

Example number

Ki (nM)

29

1.6

37

9.73

38

6.6

39

5.39

Example 53: Rodent Pharmacokinetic Study

Bibliographic reference: Millipore data sheet

Male Wistar rats (230-280 g) obtained from the NIN (National Institute of Nutrition, Hyderabad, India) were used as experimental animal. Three animals were housed in each cage. The animals were fasted for one night and kept in a 12-hour light / dark cycle. The new chemical entity (NEQ) was dosed into three rats orally (3 or 10 mg / kg) and intravenously (1 or 5 mg / kg) on day 0 and day 2.

At each time point, blood was collected from the jugular vein. The blood was stored at 2-8 ° C until analysis. The concentrations of the NEQ compound in the blood were determined using the LC-MS / MS procedure. Scheduled time points: predose, 0.08, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after dosing (n = 3). Be

10 quantified the NEQ compounds in the blood by a partially validated LC-MS / MS procedure using the acetonitrile precipitation technique. NEQ compounds were quantified in the calibration range of 1-2000 ng / ml in the blood. The study samples were analyzed using calibration samples in the batch and quality control samples spread throughout the batch.

Pharmacokinetic parameters were calculated using the non-compartmentalized model using WinNonlin software version 5.0.1.

Example number

Strain / genus Dose (mg / kg) Vehicle Route of administration Cmax (ng / ml) Tmax (h) AUCt (ng · h / ml) T1 / 2 (h) Bioavailability (%)

one

Wistar / male  one Water Intravenous 263 ± 21 1.45 ± 0.24 79 ± 11

3

Water Oral 349 ± 35 0.42 ± 0.14 626 ± 118 1.53 ± 0.41

3

Wistar / male one Water Intravenous 173 ± 60 0.56 ± 0.19 35 ± 5

3

Water Oral 129 ± 34 0.42 ± 0.14 174 ± 43 1.46 ± 0.75

eleven

Wistar / male 5 Water Intravenous 3345 ± 656 26.31 ± 5.17 20 ± 9

10

Water Oral 122 ± 55 4.0 ± 1.76 1349 ± 569 10.75 ± 1.92

19

Wistar / male one Water Intravenous 347 ± 44 17.00 ± 4.50 81 ± 12

3

Water Oral 67 ± 11 2.67 ± 1.15 838 ± 96 12.83 ± 2.48

22

Wistar / male one Water Intravenous 340 ± 60 2.04 ± 0.45 85 ± 12

3

Water Oral 376 ± 27 0.42 ± 0.14 850 ± 61 2.47 ± 0.26

5

10

fifteen

twenty

25

30

35

E11749555

09-24-2015

2. 3

Wistar / male one Water Intravenous 338 ± 29 1.13 ± 0.02 55 ± 10

3

Water Oral 389 ± 29 0.50 ± 0.00 556 ± 111 1.23 ± 0.53

37

Wistar / male one Water Intravenous 68 ± 2 3.30 ± 0.42 32 ± 8

3

Water Oral 27 ± 11 0.50 ± 0.00 64 ± 16 3.59 ± 0.43

Example 54: Rodent Brain Penetration Study

Male Wistar rats (230-280 g) obtained from the NIN (National Institute of Nutrition, Hyderabad, India) were used as experimental animals. Three animals were housed in each cage. Animals and water were procured at will throughout the experiment and kept in a 12-hour light / dark cycle.

The new chemical entity (NEQ) was dissolved in a suitable vehicle and administered orally (3 or 10 mg / kg). Approximately at Tmax (specifically at 0.5 h, 1.0 h and 2.0 h), the animals were sacrificed. Blood and brain tissue were collected and the brain homogenized, providing 20% w / v. Blood was stored at 2-8 ° C and brain homogenate was frozen at -20 ° C until analysis. NEQ concentrations in blood and brain were quantified using the LC-MS / MS procedure.

Blood NEQ and brain homogenate was quantified by the partially validated LC-MS / MS procedure using the acetonitrile precipitation technique. NEQ compounds were quantified in the calibration range of 1-500 ng / ml in blood and brain homogenate. The study samples were analyzed using calibration samples in the batch and quality control samples spread throughout the batch. The extensions of the brain-blood ratio (Ccerebro / Csangre) were calculated.

Example number

Strain / genus Dose (mg / kg) Vehicle Route of administration Brain penetration ratio (Ccerebro / Csangre)

one

Wistar / male 3 Water Oral 0.93 ± 0.05

3

Wistar / male  3 Water Oral 2.07 ± 0.07

37

Wistar / male 3 Water Oral 1.24 ± 0.18

Example 55: Object recognition task model

The cognitive enhancing properties of the compounds of this invention were estimated using this model.

Male Wistar rats (230-280 g) obtained from N. I. N. (National Institute of Nutrition, Hyderabad, India) were used as experimental animals. Four animals were housed in each cage. The animals were subjected to a 20% lack of food from a day before, they were given water at will throughout the experiment and kept in a 12-hour light / dark cycle. Rats were also accustomed to individual domains for 1 hour in the absence of any object.

A group of 12 rats received vehicle (1 ml / kg) orally and another group of animals received compound of formula (I) orally or i.p. 1 hour before the familiarization test (T1) and election (T2)

The experiment was carried out in an open field of 50 x 50 x 50 cm made of acrylic resin. In the familiarization phase (T1), the rats were placed individually in the open field for 3 minutes, two identical objects being arranged (plastic bottles 12.5 cm high x 5.5 cm in diameter) covered by masking tape yellow alone (a1 and a2) in two corners adjacent to 10 cm from the walls. After 24 hours of the long-term memory test (T1) test, the same rats were placed in the same domain in which they were placed in the T1 test. In the election phase (T2), the rats were allowed to explore the open field for 3 minutes in the presence of a familiar object (a3) and a novel object (b) (12 cm high amber glass bottle and 5 cm in diameter). Family objects had similar textures, colors and sizes. During test T1 and T2, the scans of each object (defined as sniffing, licking, chewing or movement of the vibrisas were directed by directing the nose towards the object at a distance of less than 1 cm) separately with

5

10

fifteen

twenty

25

30

35

E11749555

09-24-2015

a stopwatch Sitting on an object was not considered as an exploratory activity, however it was rarely observed. T1 is the total time spent exploring familiar objects (a1 + a2).

T2 is the total time spent exploring the familiar object and the novel object (a3 + b). The object recognition test was performed as described in Eonaceur, A., Delacour, J., 1988, "A new one-trial test for neurobiological studies of memory in rats -Behavioural data", Behav. Brain Res., 31, 47-59.

Example number

Dose mg / kg, oral Average scan time ± EEM (s) Inference

Family object

New object

one

0.3 mg / kg 5.56 ± 0.81 15.36 ± 1.74 Active

3

3 mg / kg 6.77 ± 0.44 12.49 ± 1.59 Active

22

1 mg / kg 7.12 ± 1.51 16.50 ± 2.37 Active

37

3 mg / kg 5.53 ± 1.67 14.18 ± 2.04 Active

Example 56: Morris Water Maze

The cognitive enhancing properties of the compounds of this invention were estimated using this model.

The water maze apparatus consisted of a circular pool (1.8 m in diameter, 0.6 m high) built with black Perspex (TSE Systems, Germany) filled with water (24 ± 2 ° C) and placed under a chamber Wide angle video to follow the animal. A 10 cm2 Perspex platform was placed 1 cm below the water surface in the center of one of the four imaginary quadrants, which remained constant for all rats. The black Perspex used in the construction of the labyrinth and the platform offered no clues inside the labyrinth to guide escape behavior. In contrast, the training room offered several clear visual clues outside the labyrinth to help the formation of the spatial map necessary for escape learning. An automated tracking system was used [Videomot 2 (5.51), TSE Systems, Germany]. This program analyzes video images acquired through a digital camera and an image capture card that determined the path length, swim speed and the number of entries and duration of the swim time spent in each quadrant of the water maze.

Example number

Reversal of scopolamine-induced amnesia

one

≤ 1 mg / kg oral

Example 57: Inhibition of food intake

The anti-obesity properties of the compounds of this invention were estimated using this model.

The experiment consisted of 6 days. The rats were adapted to the pattern of 18 hours of fasting and 6 hours of feeding. The animals were housed in a group of three in the cages provided with fasting gratings and fasted for 18 hours. After 18 hours of fasting, the rats were separated and placed individually in the cage. A heavy amount of feed was provided to the rats for 6 hours and the food intake was measured at 1 hour, 2 hours, 4 hours and 6 hours.

The rats were regrouped again and fasted for 18 hours. The above procedure was followed for 5 days. The average cumulative food intake by rats in the last 3 days was calculated. The animals were randomized based on their food intake the previous three days. On the day of the experiment, the rats were treated orally with test compound or vehicle. After 60 minutes, the rats were fed and the food intake was measured at 1 hour, 2 hours, 4 hours and 6 hours. The feed intake of the rats with test compound was compared with the vehicle treated group using the mismatched Student t-test.

E11749555

09-24-2015

Example number

Inhibition of food intake

13

30 mg / kg oral

16

 30 mg / kg oral

twenty-one

 30 mg / kg oral

22

60 mg / kg oral

Claims (8)

image 1 1. A compound of general formula (I): image2 in which at each occurrence, R1 is independently selected from hydrogen, hydroxyl, hydroxyalkyl, halogen, alkyl, alkoxy, halogenoalkyl, halogenoalkoxy, cyano or -C (O) -NH2; image3 L is alkyl or X is C, O or N-R2; 10 Y is C or N; A is -C (O) -o -CH2; R2 is hydrogen, alkyl, -C (O) -alkyl or -S (O) 2-alkyl; "r" is an integer in the range of 0 to 1; "p" is an integer in the range of 0 to 3; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein R1 represents hydrogen, halogen, halogenoalkyl, hydroxyl or alkyl. 3. The compound according to claim 1, which is selected from the group consisting of: N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (morpholin-4-yl) acetamide dihydrochloride; 2- [4- (1-Cyclobutylpiperidin-4-yloxy) phenylamino] -1- (morpholin-4-yl) ethanone hydrochloride; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-fluorophenyl] -2- (morpholin-4-yl) acetamide dihydrochloride; N- [4- (1-Cyclobutylpiperidin-4-yloxy) benzyl] morpholin-4-ylamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -3-fluorophenyl] -2- (morpholin-4-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-methylphenyl] -2- (3,3-difluoropyrrolidin-1-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-trifluoromethylphenyl] -2- (piperidin-1-yl) acetamide; N- [4- (1-Cyclopentylpiperidin-4-yloxy) phenyl] -2- (morpholin-4-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-trifluoromethylphenyl] -2- (morpholin-4-yl) acetamide; N- [4- (1-Isopropylpiperidin-4-yloxy) -2-methylphenyl] -2- (pyrrolidin-1-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-methylphenyl] -2- (pyrrolidin-1-yl) acetamide; N- [4- (1-Cyclopentylpiperidin-4-yloxy) -2-methylphenyl] -2- (piperidin-1-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-methylphenyl] -2- (piperidin-1-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -N-methyl-2- (morpholin-4-yl) acetamide; N- [4- (1-Cyclopentylpiperidln-4-yloxy) -2-methylphenyl] -2- (R-2-methylpyrrolidin-1-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-methylphenyl] -2- (R-2-methylpyrrolidin-1-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-methoxyphenyl] -2- (morpholin-4-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-trifluoromethylphenyl] -2- (4-hydroxypiperidin-1-yl) acetamide; image4 5 N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (4-hydroxypiperidin-1-yl) acetamide; N- [4- (1-Cyclopentylpiperidin-4-yloxy) -2-fluorophenyl] -2- (morphoIin-4-yl) acetamide dihydrochloride; N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (pyrrolidin-1-yl) acetamide; N- [4- (1-Isopropylpiperidin-4-yloxy) phenyl] -2- (morpholin-4-yl) acetamide; N- [4- (1-Cyclopropylpiperidin-4-yloxy) phenyl] -2- (morpho-4-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (4-isopropyl [1,4] diazepan-1-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (2-hydroxymethylmorpholin-4-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -3- (morpholin-4-yl) propionamide; N- [4- (1-Cyclopentylpiperidin-4-yloxy) phenyl] -2- (piperidin-1-yl) acetamide dihydrochloride; N- [4- (1-Cyclopentylpiperidin-4-yloxy) phenyl] -2- (pyrrolidin-1-yl) acetamide dihydrochloride; N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (piperidin-1-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-trifluoromethylphenyl] -2- (pyrrolidin-1-yl) acetamide dihydrochloride; N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -N- {2-morpho-4-ylethyl) acetamide; [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] - (2-morpholin-4-ylethyl) amine; L (+) - N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (R-2-hydroxymethylpyrrolidin-1-yl) acetamide tartrate; 20 N- [2- (1-Cyclobutylpiperidin-4-yloxy) pyridin-5-yl] -N- [2- (morpho-4-yl) ethyl] acetamide; N- [2- (1-Cyclobutylpiperidin-4-yloxy) pyridin-5-yl] -2- (piperidin-1-yl) acetamide; N- [2- (1-Cyclobutylpiperidin-4-yloxy) pyridin-5-yl] -2- {morpho-4-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-fluorophenyl] -N- [2- (morpholin-4-yl) ethyl] acetamide; L (+) - N- [4- (1-cyclopropylpiperidin-4-yloxy) phenyl] -N- [2- (morpholin-4-yl) ethyl] acetamide tartrate; N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (1-acetylpiperazin-4-yl) acetamide dihydrochloride; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-methylphenyl] -2- (4-hydroxypiperidin-1-yl) acetamide; N- [4- (1-Cyclopropylpiperidin-4-yloxy) feniI] -2- (R-2-hydroxymethylpyrrolidin-1-iI) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) benzyl] -2- (morpholin-4-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-fluorobenzyl] -2- (morpholin-4-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (3-hydroxyazetidin-2-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy-2-fluorophenyl] -2- (3-methoxyazetidin-1-yl) acetamide; N- [4- (1-cyclobutylpiperidin-4-yloxy) -2-fluorophenyl ] -2- (2-hydroxymethylpyrrolidin-1-yl) acetamide; N- [2-chloro-4- (1-cyclobutylpiperidin-4-yloxy) phenyl] -2- (morpholin-4-yl) acetamide; N- [ 2-Chloro-4- (1-cic! Obutilpiperidin-4-yloxy) phenyl] -2- (piperidin-1-yl) acetamide; N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl] -2- (tetrahydropyran-4-yloxy) acetamide; 2- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-fluorophenylamino] -1- (morpholin-4-yl) ethanone; Y image5 N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-fluorophenyl] -N- (2-morpholin-4-ylethyl) acetamide and its pharmaceutically acceptable salts. 4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 and pharmaceutically acceptable excipients. The pharmaceutical composition according to claim 4 for use in the treatment of clinical conditions mediated by the H3 receptor, such as cognitive disorders, dementia, attention deficit hyperactivity disorder, schizophrenia, epilepsy, sleep disorders, apnea of the sleep, obesity, eating disorders and pain. 6. A process for the preparation of a compound of formula (I) according to claim 1, comprising: 10 (a) coupling the compound of formula (1) with the compound of formula (2) image6 to form a compound of formula (I) in which all substitutions are as defined in claim 1, (b) optionally converting the compound of formula (I) into its pharmaceutically acceptable salts. A process for the preparation of a compound of formula (I) according to claim 1, comprising: (a) convert the amine compound of formula (1) image7 in the compound of formula (3), image8 20 (b) coupling the compound of formula (3) with the compound of formula (4), image9 to form a compound of formula (I) in which all substitutions are as defined in claim 1, (c) optionally converting the compound of formula (I) into its pharmaceutically acceptable salts. 8. A process for the preparation of a compound of formula (I) according to claim 1, comprising: (a) coupling of the compound of formula (5) with the compound of formula (4) image10 to form a compound of formula (6), image11 10 (b) conversion of the compound of formula (6) to form the compound of formula (I), wherein all substitutions are as defined in claim 1, (c) optional conversion of the compound of formula (I) into its pharmaceutically acceptable salts.

9.

A compound according to any one of claims 1 to 3 for use as a medicament.

10.

A compound according to any one of claims 1 to 3 for use in the treatment of

15 clinical conditions such as cognitive disorders, dementia, attention deficit hyperactivity disorder, schizophrenia, epilepsy, sleep disorders, sleep apnea, obesity, eating disorders and pain. 11. A compound according to any one of claims 1 to 3 for use in the treatment of a central nervous system disorder related to or affected by the H3 receptor.